Acceleration of human prostate cancer growth in vivo by factors produced by prostate and bone fibroblasts

Martin Gleave, Jer Tsong Hsieh, Chuan Gao, Andrew C. Von Eschenbach, Leland W K Chung

Research output: Contribution to journalArticle

387 Citations (Scopus)

Abstract

Prostate cancer, the most prevalent cancer affecting men, frequently metastasizes to the axial skeleton where it produces osteoblastic lesions with growth rates often exceeding that of the primary tumor. To evaluate the role of tumor cell-host stromal interaction and stromal specific growth factors (GFs) in prostate cancer growth and progression, we coinoculated athymio mice with human prostate cancer cells (LNCaP) and various nontumorigenic fibroblasts s.c. LNCaP tumor formation was most consistently induced by human bone (MS) fibroblasts (62%), followed by embryonic rat urogenital sinus mesenchymal (rUGM) cells (31%) and Noble rat prostatic fibroblasts (17%), but not by NIH-3T3, normal rat kidney, or human lung CCD16 fibroblasts. Carcinomas formed preferentially in male hosts, demonstrating in vivo androgen sensitivity. The human prostate component of these tumors was confirmed with immunohistochemical staining for prostate-specific antigen (PSA), Northern analysis for PSA expression, and Southern analysis for human repetitive Alu sequences. Elevations in serum PSA paralleled the histomorphological and biochemical findings. LNCaP and fibroblast cell-conditioned media (CM) was used to determine whether autocrine and paracrine mitogenic pathways exist between LNCaP and fibroblast cells in vitro, and various defined GFs were tested to identify possible active factors. Mitogenic assays revealed a 200-300% bidirectional stimulation between LNCaP and bone or prostate fibroblast-derived CM. Lung, normal rat kidney, and 3T3 fibroblast CM were not mitogenic for LNCaP cells. Among the purified GFs tested basic fibroblast growth factor (bFGF) was the most potent mitogen, stimulating LNCaP growth 180% in a concentration-dependent manner. Transforming growth factor a and epidermal growth factor were both minimally mitogenic. Coinoculation of LNCaP cells with a slowly adsorbed matrix (Gelfoam) adsorbed with bFGF or dialyzed and concentrated rUGM or MS CM was also capable of inducing LNCaP tumor formation in vivo. These observations illustrate that fibroblasts differentially modulate prostate cancer growth through the release of paracrine-mediated GFs, possibly including bFGF, and that tumor-stromal cell interactions play an important role in prostate cancer growth and progression.

Original languageEnglish (US)
Pages (from-to)3753-3761
Number of pages9
JournalCancer Research
Volume51
Issue number14
StatePublished - Jul 15 1991

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Prostate
Prostatic Neoplasms
Fibroblasts
Bone and Bones
Growth
Conditioned Culture Medium
Intercellular Signaling Peptides and Proteins
Fibroblast Growth Factor 2
Prostate-Specific Antigen
Neoplasms
Stromal Cells
Alu Elements
Absorbable Gelatin Sponge
Kidney
Lung
Transforming Growth Factors
Mitogens
Epidermal Growth Factor
Skeleton
Cell Communication

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Gleave, M., Hsieh, J. T., Gao, C., Von Eschenbach, A. C., & Chung, L. W. K. (1991). Acceleration of human prostate cancer growth in vivo by factors produced by prostate and bone fibroblasts. Cancer Research, 51(14), 3753-3761.

Acceleration of human prostate cancer growth in vivo by factors produced by prostate and bone fibroblasts. / Gleave, Martin; Hsieh, Jer Tsong; Gao, Chuan; Von Eschenbach, Andrew C.; Chung, Leland W K.

In: Cancer Research, Vol. 51, No. 14, 15.07.1991, p. 3753-3761.

Research output: Contribution to journalArticle

Gleave, M, Hsieh, JT, Gao, C, Von Eschenbach, AC & Chung, LWK 1991, 'Acceleration of human prostate cancer growth in vivo by factors produced by prostate and bone fibroblasts', Cancer Research, vol. 51, no. 14, pp. 3753-3761.
Gleave, Martin ; Hsieh, Jer Tsong ; Gao, Chuan ; Von Eschenbach, Andrew C. ; Chung, Leland W K. / Acceleration of human prostate cancer growth in vivo by factors produced by prostate and bone fibroblasts. In: Cancer Research. 1991 ; Vol. 51, No. 14. pp. 3753-3761.
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abstract = "Prostate cancer, the most prevalent cancer affecting men, frequently metastasizes to the axial skeleton where it produces osteoblastic lesions with growth rates often exceeding that of the primary tumor. To evaluate the role of tumor cell-host stromal interaction and stromal specific growth factors (GFs) in prostate cancer growth and progression, we coinoculated athymio mice with human prostate cancer cells (LNCaP) and various nontumorigenic fibroblasts s.c. LNCaP tumor formation was most consistently induced by human bone (MS) fibroblasts (62{\%}), followed by embryonic rat urogenital sinus mesenchymal (rUGM) cells (31{\%}) and Noble rat prostatic fibroblasts (17{\%}), but not by NIH-3T3, normal rat kidney, or human lung CCD16 fibroblasts. Carcinomas formed preferentially in male hosts, demonstrating in vivo androgen sensitivity. The human prostate component of these tumors was confirmed with immunohistochemical staining for prostate-specific antigen (PSA), Northern analysis for PSA expression, and Southern analysis for human repetitive Alu sequences. Elevations in serum PSA paralleled the histomorphological and biochemical findings. LNCaP and fibroblast cell-conditioned media (CM) was used to determine whether autocrine and paracrine mitogenic pathways exist between LNCaP and fibroblast cells in vitro, and various defined GFs were tested to identify possible active factors. Mitogenic assays revealed a 200-300{\%} bidirectional stimulation between LNCaP and bone or prostate fibroblast-derived CM. Lung, normal rat kidney, and 3T3 fibroblast CM were not mitogenic for LNCaP cells. Among the purified GFs tested basic fibroblast growth factor (bFGF) was the most potent mitogen, stimulating LNCaP growth 180{\%} in a concentration-dependent manner. Transforming growth factor a and epidermal growth factor were both minimally mitogenic. Coinoculation of LNCaP cells with a slowly adsorbed matrix (Gelfoam) adsorbed with bFGF or dialyzed and concentrated rUGM or MS CM was also capable of inducing LNCaP tumor formation in vivo. These observations illustrate that fibroblasts differentially modulate prostate cancer growth through the release of paracrine-mediated GFs, possibly including bFGF, and that tumor-stromal cell interactions play an important role in prostate cancer growth and progression.",
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